PB1847: A PHASE 1 STUDY TO INVESTIGATE CLN-049, A FLT3/CD3 BISPECIFIC T CELL ENGAGER, IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)
Authors: Maher Abdul-Hay, Courtney Dinardo, Onyee Chan, Rupa Narayan, Ghayas Issa, Jennifer Michaelson, Patrick Baeuerle, Kristan Meetze, John Janik, Irina Shapiro, Judy Inumerable, Jeffery Jones, David Sallman
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: CLN-049 is a humanized, IgG1-based, Fc-silenced bispecific antibody with binding specificities for FLT3 and CD3. CLN-049 effectively redirects T cells to kill FLT3-expressing malignant cells and is being developed for the treatment of patients (pts) with R/R AML or MDS. Aims: This phase 1, first-in-human study is designed to define the dosing regimen and assess the safety of CLN-049 in pts with R/R AML or MDS. Methods: The study consists of 3 parts: Part A was a single ascending dose (SAD) evaluation of intravenously (IV) administered CLN-049, Part B a multiple ascending dose (MAD) study evaluating IV administered CLN-049, and Part C a MAD study evaluating subcutaneously (SC) administered CLN-049 (NCT05143996). Because favorable pharmacokinetics (PK) are expected to mitigate the risk for cytokine release syndrome (CRS), the MAD study was initiated with SC administration. Eligible pts include adults with AML R/R to standard induction chemotherapy or venetoclax-based regimens and MDS R/R to hypomethylating agents (HMA)-based treatment. FLT3 expression on malignant cells will be measured in bone marrow (BM) and peripheral blood (PB) by flow cytometry but is not an eligibility criterion. Participants in Part A received a single IV dose of CLN-049 with safety evaluation through day 28. In Part C pts are treated with weekly SC dosing of CLN-049. Participants are hospitalized for at least 48 hours during the first administration of CLN-049 and any subsequent step-up doses (MAD only). An accelerated titration design is employed until Grade ≥2 treatment-related adverse event (TRAE), after which dosing cohorts are evaluated by standard 3 + 3 scheme. T cell and dendritic cell activation will be monitored in the PB, and levels of soluble FLT3 ligand will be tracked over time. Safety, PK, pharmacodynamic, and preliminary efficacy assessments will guide selection of the dose and schedule for further evaluation. Results: Two AML pts enrolled in Part A received a single IV dose of CLN-049 at 1.5 µg/k evaluated for safety through day 28. The first pt (baseline 47% BM blasts and receiving hydroxyurea to control leukocytosis) experienced Grade 2 CRS 5.5 hours after infusion that resolved within 24 hours with supportive care. The second pt (baseline hypocellular BM, Grade 4 leukopenia and lymphopenia, and no PB blasts) experienced no TRAE. In the first pt, measurable CLN-049 was detected and fell below the level of detection by 8 hours post-infusion. Levels of IL-6, IL-8, IL-10, and MCP1 increased above baseline at 6 hours post-infusion. No CLN-049 was detectable in the second pt and minimal cytokine levels were observed. No anti-drug antibodies were detected. At the time of data cut-off, one AML pt enrolled to Part C of the study received 1.5 μg/kg SC weekly x 5 doses without TRAEs prior to study drug discontinuation due to disease progression. No Grade >2 TRAEs were observed in any of the 3 pts. Summary/Conclusion: Safety and PK data from the SAD portion supported initiation of the MAD study. Measurable cytokine induction consistent with biological activity was observed at the initial IV dose level tested. Enrollment to the Part C SC dose escalation is ongoing, and updated data will be presented. Keywords: relapsed/refractory, MDS/AML, Bispecific, FLT3